As is well-known, the sympathetic nervous system (SNS) is a branch of the autonomic nervous system (ANS) and of the central nervous system (CNS) and is related to the parasympathetic nervous system (PNS).
The SNS is active at a so-called basal level and becomes active during times of stress. As such, this stress response is termed the fight-or-flight response. The SNS operates through a series of interconnected neurons. Sympathetic neurons are frequently considered part of the PNS, although many lie within the CNS. Sympathetic neurons of the spinal cord are, of course, part of the CNS, and communicate with peripheral sympathetic neurons through a series of sympathetic ganglia. For purposes of the present invention, the CNS may be viewed (see FIG. 1) as consisting of a spinal cord 10 and a sympathetic trunk 12 thereof.
The PNS is shown to the right of FIG. 1 as numeral 14. The PNS is considered an automatic regulation system, that is, one that operates without the intervention of conscious thought. As such, fibers of the PNS innervate tissues in almost every organ system, providing at least some regulatory function to areas as diverse as the diameter of the eye, gut motility, and urinary output. For purposes of the present invention, the only organs so regulated by the SNS shown are lung 16, hair follicles 18, liver 20, gall bladder 22, pancreas 24, adrenal glands 26, and management of hypertension generally. As may be noted in FIG. 1, all neurons of nerves of the thoracic vertebrae of the spinal cord pass through sympathetic trunk 12 thereof. This is known as the thoracolumbar outflow of the SNS. Therein, axons of these nerves leave the spinal cord through anterior outlets/routes thereof of the sympathetic trunk 12 and, certain groups thereof, including the groups emanating from thoracic vertebrae, reach celiac ganglion 28 before dispersing to various internal organs in the thoracic region of the body including the pancreas 24. From these internal organs occurs a flow of axons of these respective nerves to the base of the PNS at the vagus nerve 30 shown in FIG. 1, further discussed below.
To reach target organs and glands, axons must travel long distances in the body, and to accomplish this, many axons relay their message through a second process known as synaptic transmission. This entails the use of neuro-transmitters across what is termed the synaptic cleft which activates further cells known as post-synaptic cells. Therefrom, the message is carried to the final destination in the target organ, in this case the pancreas.
It is known that messages travel through the SNS in a bi-directional fashion. That is, so-called efferent messages can trigger changes in different parts of the body simultaneously to further the above referenced fight-or-flight response function of the SNS. It is noted that the PNS, in distinction to the CNS, controls actions that can be summarized as rest-and-digest, as opposed to the fight-or-flight effects of the SNS. Therefore, many functions of the internal organs are controlled by the PNS in that such actions do not require immediate reaction, as do those of the SNS. Included within these is the control of the gall bladder 22 and pancreas 24 as may be noted in FIG. 1.
It may thereby be appreciated that the autonomic nervous system includes both said SNS and PNS divisions which, collectively, regulate the body's visceral organs, their nerves and tissues of various types. The SNS and PNS must, of necessity, operate in tandem to create synergistic effects that are not merely an “on” or “off” function but which can better be described as a continuum of effect depending upon how vigorously each division must execute its function in response to given conditions. The PNS often operates through what are known as parasympathetic ganglia and includes so-called terminal ganglia and intramural ganglia which lie near the organs which they innervate, this inclusive of the pancreas.
The subject of FIG. 1 is shown in greater detail in FIG. 2 which shows extensions of the vagus nerve 30, known as the anterior and posterior vagus trunks 32 and right sympathetic trunk 33. Vagus nerve 30 and its offshoots are shown in yet further detail in FIG. 3 which also shows the pathways of the efferent fibers, afferent fibers and parasympathetic fibers of the CNS. More particularly, FIG. 3 shows the meningeal branch 34 of vagus nerve 30, the auricular branch 36, posterior nucleus 38 of the vagus nerve, superior ganglion 40 thereof, interior ganglion 42 thereof, pharyngeal branch 44, communicating branch 46 of the vagus nerve, superior cervical cardiac branch 48, inferior cardiac branch 50 and thoracic cardiac branch 52 of the vagus nerve. There may be appreciated the extensive role of the vagus nerve, its offshoots in human physiology and the many neural pathways—efferent, afferent, and parasympathetic, enabled by the functions of the vagus nerve.
As is shown in FIG. 2, many elements of the vagus extend downwardly, through vagus trunks 32, and into the other major parts of the celiac ganglion 28.
In FIG. 4 is shown the range of vagus nerve innervation which includes the pancreas.
The pancreas proper is shown in FIG. 5 together with the celiac axis 54 which extends from celiac ganglion 28. (See FIG. 2). Therefrom it may be seen that the pancreas is a large organ situated below the diaphragm, above the kidneys, to the right of the intestine, and with the circulatory system through the pancreatic duct 56.
The CNS is activated mainly by nerve centers located in the spinal cord, brainstem, and hypothalamus. Autonomic nerves are formed by nerves of efferent fibers (See FIG. 3) leaving the CNS (less the striated muscles); there are some efferent fibers that transmit information of the ANS.
Signals that fall in the autonomic ganglia spinal cord, brain stem, and the hypothalamus 78, produce appropriate reflex responses that are returned to the bodies to monitor their activities.
Functionality the (SNS) is divided into the sympathetic in which adrenaline and noradrenaline are used as neurotransmitters; formed by the SNS trunk 12 and other prevertebral ganglia attached to the front side of the aorta. These include the celiac ganglia 28, renal aortic mesenteric upper and lower. See FIGS. 1-3.
The PNS is formed by isolated ganglia that use acetylcholine as a neurotransmitter, is responsible for storing and conserving energy, and maintains the body in normal situations. It always appears as an antagonist of the SNS, controlling involuntary acts. Its nerves are carried in the cranial nerves including the vagus 30 and its offshoots, as discussed above.
The spinal cord includes the sacral roots of S2 whose neurotransmitter is acetylcholine.
Sympathetic nerves originate in the spinal cord segments T1 to T2 (see FIG. 1) of the sympathetic chain (SNS) and proceed to the tissues and organs from the neuron preganglionic. Its axons pass through the root of the spinal cord corresponding to the spinal nerves. Therefrom preganglionick sympathetic fibers pass though the branch to one of the ganglia of the SNS, such that they then take one of the two following paths:
A. To neurons synapses, postganglionic of the ganglion which it penetrates. And
B. Up and down the SNS chain to generate synapses in other ganglia at varying distances and then through one of the sympathetic nerves coming out of the chain ending in one of the pre-aortic branches 48/50 (see FIG. 3) that innervates it. The SNS originates at different segments of the spinal cord, not necessarily directed to the same parts of the body as with the somatic spinal nerve fibers coming from the same vertebrae. Thus one sees that in the spinal segment T5 is associated with the SNS chain from the head T2 to the neck including T3 to T6. See FIG. 1. T7 to T11 go to the abdomen and then T12 to L2 go to the pelvis and legs.
The distribution of the sympathetic nerves to each organ is determined by the position that of the organ in the embryo when it originates.
The PNS and its fibers enter the CNS through sympathetic trunk 33 and the Cranial Nerves III, VII, IX, and X although like the SNS, it does not have pre- and post-ganglionic neurons. See FIG. 2.
The preganglia fibers travel through, without interruption, all the way to the tissue that it innervates. In the wall of the nerves are the neurons (postganglionic). Postganglionic fibers make synapses and spread throughout the body (some 1 millimeters to a few centimeters).
The parasympathetic innervation of the intestine runs through the vagus nerve and sacral nerves in the pelvis producing among other stimulation of the exocrine secretions of glandular epithelium, with an increase in the secretion of gastrin, secretion, and insulin. See FIG. 4.
It is noted that insulin is released only by beta cells in pancreatic Islets (i.e., small isolated masses of one type of tissue within a different type), known as the Islets of Langerhans. Insulin is one of the endocrine system secretions (i.e., secretions that are distributed in the body by way of the bloodstream) of the Islets of Langerhans, which helps integrate and control bodily metabolic activity. The Islets also include alpha cells, which produce glucagon, delta cells which produce somatostatin, and a small number of PP cells which produce pancreatic polypeptide (“PP”). The beta cells tend to be in the center of the pancreatic Islets, while the alpha cells tend to occupy the periphery. The beta cells generally constitute 60-70% of the Islets, the alpha cells 20-25%, and the delta cells approximately 10% Gap junctions exist between neighboring islet cells, permitting the ready flow of molecules and electrical current between cells. If these gap junctions are disrupted, insulin secretion is markedly reduced. Islet cell clusters function better as electrical than biochemical syncytia.
Under normal circumstances, insulin is secreted by the beta cells in response to an elevated level of plasma glucose via the following steps. The transportation of glucose across the beta cell membrane is facilitated by a specific transporter molecule known as GLUT-2. Once inside the beta cell, the enzyme glucokinase causes glucose to phosphorylate (i.e., to take up or combine with phosphoric acid or a phosphorus-containing group), which prevents its efflux. High levels of glucose and glucose-6-phosphate within the cell lead to a rapid increase in the ratio of adenosine triphosphate (ATP) to adenosine diphosphate (ADP), which leads directly to the closure of ATP-sensitive transmembrane potassium ion (K+) channels. This prevents the normal efflux of K+ from the beta cell, and the cell depolarizes, i.e., closing of some ionic channels. Voltage-regulated calcium ion (Ca++) channels open in response to this depolarization, allowing an influx of Ca++. Elevated intracellular Ca++ leads to activation of protein kinases and ultimately to fusion of insulin-containing secretory granules with the beta cell membrane, thus leading to exocytosis of insulin into the systemic circulation. This entire sequence occurs within one minute of exposure to elevated glucose levels.
Insulin is a hormone that serves a variety of functions, the primary action of which is to potentiate the uptake of glucose from the bloodstream by muscle and adipose tissue. It also promotes conversion of glucose to a storage form (i.e., glucagon) in the liver and to fat in adipose tissue. These actions serve to decrease the circulating level of glucose.
Glucagon is released primarily under conditions of hypoglycemia, and it tends to have effects opposite those of insulin. Release of glucagon is also promoted by alpha-adrenergic neurotransmitters, and it is inhibited by beta-adrenergic neurotransmitters, cholinergic neutransmitters, and insulin.
Somatostatin secretion is stimulated by glucose, glucagon, beta-adrenergic neurotransmitters, cholinergic neurotransmitters, and a number of other chemical factors; its release is inhibited by insulin and by alpha-adrenergic neurotransmitters. Somatostain tends to inhibit the release of both insulin and glucagon.
Parasympathetic Stimulation
Secretion of insulin may also be modulated by other neural and chemical factors. Parasympathetic stimulation and the consequent release of acetylcholine tends to increase the secretion of insulin. Sympathetic stimulation produces competing effects, as beta-adrenergic neurotransmitters tend to increase insulin secretion while alpha-adrenergic neurotransmitters tend to decrease insulin secretion. Insulin secretion is also increased by a number of other factors, including K+, Ca++, arginine, lysine, glucagon-like peptide 1, gastric inhibitory peptide (GIP), secretion, cholecystokinin (CCK), and beta-3-agonists. Insulin secretion is also decreased by a number of other factors, including somatostatin, galanin, pancrestatin, and leptin.
As above noted, a significant body of research exists describing the influence of parasympathetic activity on insulin secretion by the pancreatic beta cells. Parasympathetic nerve stimulation in the dog produces a marked increase in insulin secretion and a moderate increase in glucagon secretion. In addition, parasympathetic activation produces increased insulin and glucagon secretion in proportion to pulse frequency, while inhibiting somatostatin release. Cholinergic neurotransmitters, which are the neurotransmitters most commonly secreted by parasympathetic nerve fibers, were found to be responsible for this influence. However, findings also suggest that a non-cholinergic neurotransmitter(s) may also be involved in parasympathetic regulation of pancreatic hormone secretion.
The specific parasympathetic pathways innervating the pancreatic Islets are known. Three branches of the vagus nerve mediate both insulin and glucagon release. The posterior gastric branch (198% and 117% increase from basal for insulin and glucagon, respectively), the anterior gastric branch (177% insulin increase and 104% glucagon increase), and the hepatic branch (103% insulin increase the 60% glucagon increase). In contrast, unreliable and insignificant hormonal responses were produced by electrical stimulation of fibers projecting from two other branches of the vagus nerve: the posterior celiac branch (12% insulin increase and 12% glucagon increase) and the accessory celiac branch (15% insulin increase and 31% glucagon increase).
Sympathetic Stimulation
The sympathetic nervous system also exerts a significant influence on insulin and glucagon secretion by the pancreatic Islets. The sympathetic splanchnic nerve, arising from the paraspinal sympathetic trunks, is the primary sympathetic influence on the pancreas. Its primary neurotransmitter is norepinephrine, which activates alpha-adrenergic and beta-1-adrenergic receptors, but has relatively little influence on beta-2-adrenergic receptors.
The pancreas is comprised mostly of acini and the Islets of Langerhans. Acini comprises over 80% of the gland. Each acinus is lined with wedge-shaped acinar cells. Acinar cells are the site of production and secretion of the digestive enzymes.
Capillaries allow hormones from the Islet cells to reach the acinar cells. Islets of Langerhans are scattered irregularly throughout the pancreas and contain the Islet cells, which are responsible for secreting the endocrine hormones: insulins, glucagon, somatostatin, and pancreatic, polypeptides. The insulin-secreting beta cells comprise about 60-70% of the Islet. They are surrounded by a mantle of glucagon-secreting alpha cells, somatostatin-secreting delta cells, and pancreatic polypeptide-secreting PP cells. The various cells of the Islets are separated from another by a rich capillary network.
The present invention provides electrical stimulation to at least one or more of the above mentioned areas as a treatment for diabetes. It is known that cells of the human body are acutely responsive to electrical and electromagnetic stimulation through neurotransmitters and otherwise, as has long been established by research in the area. Calcium has been determined to be the final transmitter of electrical signals to the cytoplasm of human cells. More particularly, changes in cell membrane potential are sensed by numerous calcium-sensing proteins of cell membrane which determine whether to open or close responsive to a charge carrying elements, in this case, the calcium anion Ca2+. This is shown conceptually in FIG. 6 which shows the electrical call-to-action of a cell upon its sensing of a voltage gradient carried or created by a calcium anion. Stated otherwise, calcium anions transduce electrical signals to the cells through what are termed voltage-gated calcium channels (see Hille, “Ion Channels of Excitable Membranes,” 3 Ed., 2001, Chap. 4). It is now recognized that electrical signaling of voltage-gated channels (of which there are many categories) of human cell membranes is controlled by intracellular free calcium (and other) ionic concentrations, and that electrical signals are modulated by the flow of calcium and other anions into cytoplasm from the external medium or from intra cellular stores through ionic specific channels.
These channels act as gates, in which concept of an “ion channel” was first proposed in the year 1950, that these channels represent a wide variety of biological processes, and rapid changes in the cells:
Contraction of the muscle, transport of nutrients, activation of (T) lymphocytes, the release of insulin by the beta cells of the pancreas, and cellular osteogenesis occur.
Differentiation, remodeling or hypertrophy, among other functions also occur. Ionic channels have two important characteristics:
1. Conduction of ions.
2. Recognition and selection of ions.
When changes occur in the voltage across a membrane, some channels are opened by electrical stimulus, or they may respond to chemicals, drugs or hormones.
Neurotransmitters, or may be activated by ligands. If there are changes in temperature or deformation by narrowing, widening of the membrane, they may be opened and mechanically.
Some ionic channels are opened or closed randomly regardless of the value of the membrane potential in which it is said that this “gating” is independent of voltage. However, certain ionic channels control membrane potential. When such channels are open, they can conduct electric current allowing ions to pass through the cytoplasmic membrane of the cell. These ions generate a current and establish an electromechanical gradient either positive or negative, depending charges on the ions, their quantity of direction, inward or outward, and the structure of the cytoplasmic membrane itself. Involved are different processes of activation, deactivation, inactivation, and finally reactivation.
Activation is the process of opening up the cell channels, responsive to the fact that the voltage within the cell membrane is more positive with respect to the outside. This is knows as depolarization.
Deactivation is the opposite process, which relates to the closing of a channel responsive to reversal of membrane potential.
Voltage of the interior of the membrane becoming more negative this is known as repolarization.
Inactivation relates to the closing of the channels during deactivation and occurs as the interior of the membrane is more positive. However, there is always a delay with respect to activation of a channel. As suggested above, a difference of voltage between the sides of a channel of a cell membrane causes the voltage gradient across said channels, also known as the current gate.
Some of these channels have a “refractory” aspect, also known as an inactive channel and is believed to be caused by an opening of a sub-unit of the channel.
The inventors believe that the flow of electrons or existence of the electrons of a voltage gradient for a longer time and, therefore, in a greater quantity, enhances activation, causing a greater exchange of ions and more effective control of membrane potential, enhancing intracellular currents from the stage of repolarization by giving them more time to the cell to react. See FIG. 7, as discussed below. One must also remember that the function of excitable cells depends on the entry of Na+ at an intensity of +61 mV, via Na channels, when activated. This entry of Na+ produces a depolarization of the membrane potential, facilitating the opening of more channels to the Na+ potential for 1-2 milliseconds. When at rest the cells of Na+ ions cause little opening and therefore cause inactivation of the Na channels.
The proteins associated with the extracellular K+ channels cause depolarization, that is, these channels are facilitated by the output of K+ ion about 90 Mv of the cell which contributes to the polarization of the membrane potential, and its rest potential of 90MV this activity automatically triggers the cells and helps the release of neurotransmitters, insulin secretion, cell control of membrane potential.
Excitability, transportation of electrolyte and muscle contraction affect regulation of cell volume as do the channels of Na+. There exist K+ channels, which influence the membrane potential and causes potential of rest and regulation of the volume of intracellular liquid. These channels can be similarly modified as to the time and the quantity of the flow of electrons effected by the inventive treatment including variables of frequency, pulse, wavelength of applied stimulation.
In resting cells, the intracellular concentration of Ca2+ is 20,000 times less at rest than outside. That is Ca2+ is too low but is permeable with activation.
The membrane potential caused by the output of the K+ and its reactivation of channels produces a repolarization of the membrane, thus obtaining an input of Ca2+ for each K+ that exists out of the cell.
Intracellular Ca2+ is important in many biological processes including the potential for action, duration of action, excitability and contraction, release of neuro-transmitters, release or hormones, release of growth factors, synaptogenesis, osteogenesis, process of cell differentiation, hypertrophy, remodeling and increase of the release of insulin to the beta cells of the islets of the pancreas, including the breaking of the intracellular vesicles that there are stored with insulin. Process our treatment is largely based on this process.
Other important channels are those of calcium also regulate cellular excitability and its transmembrane by regulating the cellular pH and volume of influx.
One well-studied calcium dependent process is the secretion of neuro-transmitters at nerve terminals. See Hille, page 104 thereof. Within the presynaptic terminal of every chemical synapse, there are membrane-bounded vesicular-containing high concentrations of neurotransmitter molecules of various types. When such an action potential engages a neurotransmitter, the membranes having one or more of these vesicles in their surface membrane, release a group of neuro-transmitters into the cellular space. This is conceptually shown in FIG. 6. In the pancreas, there exist the above noted pancreatic acinar cells which contain zymogen granules which assist in cellular functions thereof.
Normally stimulated secretion from nerve terminals of most excitable cells require that the extracellular calcium anions Ca2+ pass thru ionic channels of the cell. The above is shown at a cellular level in the schematic view of FIG. 7 which shows a calcium anion channel 58 of cell 60 as well as the egress of a potassium anion through a so-called KATP channel 62 when a calcium anion enters the cell. This process triggers a variety of functions which relate to insulin secretion. Lack of sufficient secretion is of course the primary cause of diabetes as it is broadly understood. FIG. 7 therefore illustrates the current model of insulin secretion (Ashcroft, “Ion Channels and Disease,” 2000, p. 155).
In summary, FIG. 7 indicates, in a normal functioning of the beta cell, that when plasma glucose levels rise, glucose uptake and metabolism by the pancreatic beta cells is enhanced, producing an increase in the intracellular ATP which is the primary cellular energy source. These changes act in concert to close calcium channels 62 in the beta-cell membrane because ATP inhibits, whereas MgADP (shown in FIG. 3) activates, calcium ion channel activity. In that calcium channel activity determines the beta cell resting potential, its closure causes a membrane depolarization 64 that activates voltage-gated calcium anion channels 62, increasing calcium influx and stimulating insulin release. However, insufficient charge upon intracellular calcium may, it is believed, be one cause of inhibition of the above-described normal metabolic process of the pancreatic beta cells. In other words, if intracellular calcium, or its relevant neurotransmitters, lack sufficient charge, insufficient electrical energy 86 is provided to secretory granules 68 sufficient to effect insulin release 70, that is necessary to metabolize glucose 72.
Another view of insulin secretion is that, by blockage of potassium ion channels 62, sufficient charge can be sustained within the cell to maintain normal function of secretory granules 68 and therefore of insulin release 70. Therapeutic drugs which seek to so modulate insulin secretion by control of the potassium channels are sulphonylureaus and diazoxide.
In summary, when blood glucose 72 rises, the uptake thereof is increased by the action of the calcium anions Ca2+ entering cell 60 through channels 38. Aspects of this metabolism cause the potassium ATP channels to close which results in membrane polarization 64, a change of voltage potential at calcium ion channels 58, and an increase in cytoplasmic anionic calcium that triggers the function of insulin secretory granules 68. It is therefore desirable to regulate calcium channel activity by maintaining a low level of blood glucose. But, this requires that an adequate molarity of Ca2+ exist in the beta cells.
The relationships of the offset of ionic calcium on membrane potential of the cell, ionic current flow within the cell, and molarity of calcium within the cell are shown in FIGS. 8 and 9 respectively. FIG. 10 indicates that the percent of time of calcium channel opening as a function of membrane potential and calcium molarity within the intracellular media. Stated otherwise, an increase in membrane potential will increase the time that voltage-gated ionic channels of the cell are open. In view of the above, it appears an appropriate increase in ionic calcium within beta cells of the pancreas will bring about an increase in insulin release if supported by a sufficiency of the membrane potential. The cross-hatched area 74 at the top of the graph of FIG. 10 represents a confluence of parameters most beneficial to the health of the beta cells.
It is to be appreciated that the channels of K+ are dependent on the level of ATP and therefore of glucose in blood will be closed and the cell membrane is depolarized; with this, dependent Ca2+ channels of voltage are opened and the Ca2+ enters the cell. This increase in intracellular Ca2+ activation produces phospholipase that divides the phospholipids in the membrane phosphatidylinositol 1,4,5 triphosphate and diaclyglycerol. The inositol 1,4,5-triphosphate (IP3) to protein receptors on the membrane of the endoplasmic reticulum allow the release of the Ca2+ (ER) via the channels increasing the intracellular concentrations of Ca2+.
These amounts of Ca2+ increased are responsible for causing activation of the synaptotagmin, which helps to release insulin previously stored in the vesicles. With this being the main mechanism for the release of insulin.
Other substances induce the release of the hormone, amino acids, acetylcholine, which is released from the stimulation of the terminations of the vagus nerve (30). Our treatment stimulates the paraverterbral ganglia and the superior mesenteric ganglion 40 (see FIG. 3) which stimulate enteroendrocrine cells of the intestinal mucosa by freeing cholecystokinin that acts to release insulin. There are three amino acids, lysine, glycine, and arginine that act with the same mechanism from glucose in the blood, all of which activate the cellular membrane potential, that is, increase the permeability of ionic channels in the beta cells and produce an increase in insulin release. The autonomic nervous system (ANS), as above noted, controls involuntary action, receives information from visceral parts of the brain, and the internal environment, to act on the muscles, glands, and blood vessels, is an efferent system (see FIG. 3), transmitting impulses from the CNS up to the periphery's stimulating many peripheral elements.
We have seen the activation of ion channels by voltage gradients, but there are other controls of membrane potential.
Other means of activations of ion channels include, for example, the ligands, which are produced by the interaction of neurotransmitters and hormones, with a portion of the channel receptor, which causes a cascade of enzymatic events and phosphorylation, all of which produce the necessary energy to keep the channels open or closed, as needed. Enabling receptors are located inside and outside of layers of the membrane and according to the electrical charges of proteins (positive or negative), depending on the existing gradient at a given channel.
There are channels which are regulated by mechanical action that are directed by Pacinian corpuscles (PC). Such membranes open by stretching and/or contraction.
As a conclusion to the above, we see that the ionic channels occur in a wide variety of biological processes which require rapid changes in the cell, for example: Heart muscle contraction, transport of ions and nutrients through the epithelium, and T lymphocyte control of membrane
Activation and release of insulin by the beta cells of the Islets of the pancreas comprises our key objectives in the search for new methods and/or treatments to improve and to cure a number of pathological processes.
As in Type II Diabetes Mellitus (T2D) ions passing through the cytoplasmic membrane for their normal metabolism have been discovered to exist in all human cells, functioning as a “biological clock.” Researchers from the University of California, at Irvine have reported important findings in day/night cycles and its relationship to metabolism and cellular energy, and have also suggested new treatments for cancer, obesity, and other diseases. Such circadian rhythms of 24 hours govern or direct fundamental physiological functions in almost all living organisms.
Sassone-Corsi discovered the relationship of proteins to a “protein clock” that modulates energy levels involved in the metabolism, equilibrium, and cellular aging. An imbalance in this process can cause disease. And other imbalances and therefore stimulus can induce lead or lag in the biological clock using effects of pulsed light and darkness during a 24-hour period to thus influence hormonal secretions of the glands in range of one to two hours, resulting in a system of internal regulation of the time. As such, nutritional factors, environment, and cycles of light/dark all influence the life of the cell and therefore the organism. This organization of time is altered in many pathophysiological conditions such an aging and endocrine diseases.
Researchers (the neuroscientist at the Cambridge University, Dr. Akhelesh Reddy) discovered a circadian oscillator in mammals located in suprachiasmatic nucleus 76 of the anterior hypothalamus 78 provides information of the physiological processes of the body, the operation of which is genetically pre-programmed. See FIG. 11. This postulates the necessity of a stable biological clock for healthy living in the early hours of the morning and considered ideal for work of concentration, the afternoon for manual work, and until the end of the afternoon for the proactive of sports where more energy is released by the cell. That is why our treatment, as below described, must be applied after 11:00 a.m. and before 8:00 p.m.
The period since about 1983 has witnessed a dramatic increase in the prevalence in patients of a cluster of inter-related metabolic disease stages, primarily caused by obesity and immune disease stages, jeopardizing homeostasis and leading to the diabetic state. The incidence of diabetes, with or without obesity, has reached epidemic proportions, bringing with it impaired quality of life and life span due to serious clinical co-morbidities such as peripheral vascular and neuropathic disease, with or without pain, ulcerative skin lesions often leading to infection, gangrene, and amputation, vision loss, cardiac and renal failure and brain disorders. Without question, chronic disease associated with diabetes represents a heavy and growing burden to society in terms of both direct healthcare costs that have reached catastrophic levels and mortality rates (American Health Rankings, 2010 edition).
According to American Diabetes Association, as of 2010, 23.6 million children and adults, approximately 8% of population in the United States (US), have diabetes, and over 57 million people are clinically considered pre-diabetic in the US. According to United HealthCare, based on current trends, 52% of the US adult population could have pre-diabetes or diabetes by 2020—up from an estimated 40% in 2010, resulting in costs estimated at $3.4 trillion for diabetes-related care over the decade from 2010 to 2020. The incident of Type 2 diabetes (T2D) in adolescents has increased 10 fold from 1982 to 1994 (Pinhas-Hamiel 1996). Over 25% of obese children are considered glucose intolerant. Insulin resistance is related to inflammation and obesity induces a stage of chronic inflammation. In obese stages, adipose tissue secretes inflammatory agents such as cytokines. Adipose tissue macrophages adversely alter insulin sensitivity in animal models. Obesity can be reframed as an inflammatory disease, with macrophages acting at the junction between over nutrition and inflammation.
Provided herein are methods, systems and apparatuses for preserving, restoring or affecting pancreatic beta cell function in a subject. These methods include electrically stimulating C-afferent sensory nerve fibers innervating pancreatic beta cells but originating in the spinal cord in a subject, in which the electrical stimulation modulates a secretion of calcitonin gene-related peptide (CGRP) from the C-afferent sensory nerve fibers (see FIG. 3); determining a level of a biomarker in the subject and repeating the electrical stimulation as a function of the level of the biomarker.
With respect to the prior art as is know to the within applicants, U.S. Patent Application Publication US2002/00026141 (2002) to Houben et al, teaches a system for pancreatic stimulation and glucose measurement. Houben relates to an implantable insulin pump and, as such, is representative of various implantable or other insulin pumps which have been suggested over the last 40 years. The system, as disclosed herein, is not implantable and operates strictly through neurophysiologic stimulation to the spine and associated areas.
U.S. Pat. No. 4,477,944 (2009) to Whitehurst et al, teaches Methods and Systems for Modulation of Pancreatic Endocrine Secretion and Treatment of Diabetes. It, like Houben, is an implantable system, and, as such, simply reflects an improvement of Houben.
U.S. Patent Application Publication US2011/0230939 (2011) to Weinstock, teaches a system for diagnosis and treatment of diabetes. The system of Weinstock, while not implantable, does not make use of the same neurophysiologic waveforms or treatment strategy as is taught by the within invention.
WIPO Publication No. WO 2012/083259 to Perryman teaches a Method, System and Apparatus for Control of Pancreatic Cell Function to Improve Insulin Production. Perryman teaches a method of nerve innervation of the pancreas which includes an implantable system but also purports to teach a non-implantable system. However, the bioelectric method of the nerve stimulation of the pancreas of Perryman bears no relationship to that taught by the instant invention.